The present invention relates to certain compounds having cytoprotective activity, and particularly to a series of benzofuran derivatives. The invention is also directed to formulations and methods for treating stroke, myocardial infarction and chronic heart failure, as well as other oxidative stress-related conditions that are typically responsive to cellular enzyme modulation. The invention is also directed to a method of treating inflammation by reducing C-reactive protein (CRP). The invention is also directed to cosmetic formulations for the treatment of skin inflammation and other skin disorders.
The present invention is concerned with cytoprotective compounds, which are benzofuran derivatives, said derivatives including steroisomers, mixtures of stereoisomers and therapeutically acceptable salts therof.
Compositions of the invention are active in certain experimental models that predict efficacy in, for example, certain ischemic or inflammatory conditions, including but not limited to stroke, myocardial infarction, congestive heart failure, and skin disorders characterized by inflammation or oxidative damage. The invention is therefore related to the use of the cytoprotective derivatives in such conditions.
2,3-Dihydro-5-oxy-4,6,7-trimethyl-2-optionally substituted alkyl benzofurans have been disclosed as antioxidizing pharmaceutical products having anti-ischemic properties in U.S. Pat. No. 5,114,966. Hydroxamines derivatives of 2,3-dihydrobenzofuran carboxy acids have been disclosed in U.S. Pat. No. 5,480,645. 2,3-Dihydrofuran derivatives useful in preventing and treating neovascularization have been disclosed in U.S. Pat. No. 5,719,167 and U.S. Pat. No. 5,798,356. 5-Hydroxybenzofurans have been disclosed for the treatment of a pathological cell proliferative disease in U.S. Pat. No. 5,674,876. A method of inhibiting mammalian leukotriene biosynthesis with 6-hydroxybenzofurans has been disclosed in U.S. Pat. No. 4,714,711.
While various agents have heretofore been provided for such conditions, it has, however, remained desired to provide new therapies for conditions characterized by oxidative stress, and particularly, for providing protection in the event of cerebral ischemia, ultraviolet exposure or inflammation; especially desired are agents that are effective even if first administered after a significant period of time (e.g., about 5 or more hours) following an ischemic or oxidative insult.
The present invention is concerned with certain novel and related cytoprotective compounds that are particularly active in restoring or preserving metabolic integrity in oxidatively competent cells that have been subjected to oxygen deprivation. Such compounds, predominantly benzofuran derivatives are useful in the manufacture of pharmaceutical compositions for treating a number of conditions characterized by oxidative stress, and particularly, in providing protection in the event of cerebral ischemia, ultraviolet exposure, or inflammation, even when administered a significant time interval after an ischemic or oxidative insult. In particular, the compositions of the present invention are useful in the treatment of stroke, as demonstrated by providing neuroprotection in a standard experimental model of focal cerebral ischemia. They are also useful in the treatment of myocardial ischemia (myocardial infarction), as well as other indications characterized by oxidative stress and/or inflammation, including, but not limited to, diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, chronic heart failure, rheumatoid arthritis, muscle fatigue, intermittent claudication, and for the preservation of allograft tissue for transplantation. Particularly with regard to dermatological conditions, the compounds, formulations and methods of the present invention are useful in regulating skin condition, regulating the signs of skin aging, and in treating a number of conditions, including, but not limited to preventing and protecting skin tissue against age-related damage or damage resulting from insults such as harmful (UV) radiation, stress and fatigue. These compounds, formulations and methods of the present invention are also useful in the treatment for example of contact dermatitis, acne, irritation including retinoid induced irritation, hirsutism, modulation of hair growth, disorders in pigmentation, or psoriasis, and can be used as bactericides, antifungal and antimicrobial agents. The compounds of the present invention also show activity for reducing elevated CRP levels associated with a number of diseases and disorders, including but not limited to, cardiovascular disease, diabetes and infectious diseases.
The present invention concerns the compounds represented by the Formula I: 
wherein:
R1 is: hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, (optionally substituted alkoxy)carbonyl, or halogen;
R2 and R3 are independently selected from optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted cycloalkyl;
R4 is: hydrogen, optionally substituted aryl, (optionally substituted alkyl)carbonyl, (optionally substituted aryl)carbonyl, (optionally substituted heterocyclyl)carbonyl, (optionally substituted heterocyclylalkyl)carbonyl, (optionally substituted alkoxy)carbonyl, (optionally substituted alkenyloxy)carbonyl, (optionally substituted amino)carbonyo, carboxy, formyl, or hydroxy(optionally substituted)alkyl;
R5 is: hydrogen, alkyl, alkenyl, (optionally substituted alkoxy)carbonyl, carboxy, (optionally substituted amino)carbonyl, or optionally substituted aryl;
provided that one of R4 or R5 is hydrogen, and that when R4 is hydrogen R5 is not hydrogen, and when R5 is hydrogen R4 is not hydrogen;
R is hydrogen, alkyl, acyl, phosphoryl, or polyalkoxy; or
R and R1 with the atoms to which they are attached form an optionally substituted ring;
including single stereoisomers, mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof.
A preferred embodiment of this invention concerns the compounds of Formula I where R2 and R3 are (C1-C6)-alkyl, preferably methyl, and within that subset those compounds of Formula I wherein R is hydrogen.
In another embodiment, the invention concerns the compounds of Formula I wherein R2 and R3 are (C1-C6)-alkyl, preferably methyl, R is hydrogen, R5 is hydrogen, and R4 is optionally substituted aryl, (optionally substituted alkyl)carbonyl, (optionally substituted aryl)carbonyl, (optionally substituted heterocyclyl)carbonyl, (optionally substituted heterocyclylalkyl)carbonyl, (optionally substituted alkoxy)carbonyl, (optionally substituted alkenyloxy)carbonyl, (optionally substituted amino)carbony), carboxy, formyl, or hydroxy(optionally substituted)alkyl, especially wherein said aryl is unsubstituted phenyl or substituted phenyl with one or more substitutents selected from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano.
In another embodiment, the invention concerns the compounds of Formula I wherein R2 and R3 are (C1-C6)-alkyl, preferably methyl, R is hydrogen, R4 is hydrogen, and R 5 is optionally substituted aryl, preferably unsubstituted phenyl or phenyl substituted with one or more substitutents selected from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano.
In another embodiment, the invention concerns the compounds of Formula I wherein R2 and R3 form a ring, preferably R and R1 form a furan ring substituted with an unsubstituted phenyl or with a phenyl substituted with one or more substitutents selected from alkyl, alkenyl, hydroxy, alkoxy, nitro, cyano, carboxy, carboxyester, haloalkyl, and halo.
Certain embodiments of the invention provide novel and preferred combinations of the substituents groups pendant from the formulae of the different inventions.
In another aspect, the invention relates to pharmaceutical and/or cosmetic compositions containing a therapeutically effective amount of a compound of any of Formula I, or a pharmaceutically acceptable salt thereof, admixed with at least one pharmaceutically acceptable excipient. Particularly preferred are those pharmaceutical or cosmetic compositions wherein a compound of Formula I is selected from the Preferred Compounds.
Another aspect of the present invention concerns methods of treatment for a mammal suffering from a condition characterized by oxidative stress by administering a therapeutically effective amount of a compound represented by the Formula I including single stereoisomers, mixtures of stereoisomers, and the pharmaceutically acceptable salts thereof.
In one embodiment, the invention relates to a method of treatment of a cardiovascular, cerebrovascular, neurologic, inflammatory, autoimmune, and/or dermatologic condition. In another embodiment the invention relates to a condition selected from stroke, cerebral ischemia, myocardial infarction, chronic heart failure, retinal ischemia, post-surgical cognitive diysfunctions, peripheral neuropathy, spinal cord injury, head injury and surgical trauma. In another embodiment the condition involves inflammatory or automimmune components.
In another embodiment, the invention relates to a method for treating dermatologic conditions characterized by oxidative stress including but not limited to regulating skin condition, regulating the signs of skin aging, contact dermatitis, acne, skin pigmentation, hair growth modulation, irritation including retinoid induced irritation, psoriasis, age-related damage and damage resulting from harmful (UV) radiation, stress, or fatigue. In another embodiment the compound of Formula I or composition thereof, is administered topically. In another embodiment the condition is dermatologic, further comprising a method of promoting a product by directing a user to apply to the skin a pharmaceutical or cosmetic composition incorporating said compound of Formula I.
In still another embodiment, the invention relates to a method of treating stroke and other oxidative stress-related conditions that are responsive to cellular enzyme modulation such as cerebral ischemia, myocardial infarction, chronic heart failure, and exposure to UV radiation in a mammal, by administering to a mammal in need of such treatment a therapeutically effective amount of a compound of any of Formula I, or a pharmaceutically acceptable salt thereof.
In still another aspect, the invention relates to a method of reducing levels of C-reactive protein (CRP) associated with inflammation, including but not limited to cardiovascular inflammatory condition, respiratory inflammatory condition, sepsis, diabetes, muscle fatigue, systemic lupus erythematosis (SLE), end stage renal disease (ERSD), periodontal disease, and inflammatory skin conditions.
Particularly preferred are those methods of treatment and uses in the manufacture of pharmaceutical and/or cosmetic compositions therefor, wherein a compound of Formula I is selected from the Preferred Compounds.
As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.
The term xe2x80x9coptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, xe2x80x9coptionally substituted alkylxe2x80x9d means either xe2x80x9calkylxe2x80x9d or xe2x80x9csubstituted alkyl,xe2x80x9d as defined below. It will be understood by those skilled in the art with respect to any group containing one or more substituents that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical and/or synthetically non-feasible.
Certain compound, reactant, or reaction parameter abbreviations are defined as follows:
xe2x80x9cDCMxe2x80x9d refers to dichloromethane or methylene chloride
xe2x80x9ct-Buxe2x80x9d refers to t-butyl
xe2x80x9cDCCxe2x80x9d refers to 1,3-dicyclohexylcarbodiimide
xe2x80x9cDICxe2x80x9d refers to N,N-diisopropylcarbodiimide
xe2x80x9cDIPEAxe2x80x9d refers to diisopropyl ethylamine
xe2x80x9cDMAPxe2x80x9d refers to 4-N,N-dimethylamino pyridine
xe2x80x9cDMFxe2x80x9d refers to N,N-dimethyl formamide
xe2x80x9cEq.xe2x80x9d refers to equivalent
xe2x80x9cEDCIxe2x80x9d refers to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
xe2x80x9cMeOHxe2x80x9d refers to methanol
xe2x80x9cTHFxe2x80x9d refers to tetrahydrofuran
xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate.
The term xe2x80x9cacylxe2x80x9d refers to the groups xe2x80x94C(O)xe2x80x94H, xe2x80x94C(O)-(optionally substituted alkyl), xe2x80x94C(O)-(optionally substituted cycloalkyl), xe2x80x94C(O)-(optionally substituted alkenyl), xe2x80x94C(O)-(optionally substituted cycloalkenyl), xe2x80x94C(O)-(optionally substituted aryl), xe2x80x94C(O)-(optionally substituted heteroaryl) and xe2x80x94C(O)-(optionally substituted heterocyclyl).
The term xe2x80x9calkenylxe2x80x9d refers to a monoradical branched or unbranched, unsaturated or polyunsaturated hydrocarbon chain, having from about 2 to 20 carbon atoms, more preferably about 2 to 10 carbon atoms. This term is exemplified by groups such as ethenyl, but-2-enyl, 3-methyl-but-2-enyl (also referred to as xe2x80x9cprenylxe2x80x9d), octa-2,6-dienyl, 3,7-dimethyl-octa-2,6-dienyl (also referred to as xe2x80x9cgeranylxe2x80x9d), and the like.
The term xe2x80x9csubstituted alkenylxe2x80x9d refers to an alkenyl group in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is replaced by a substituent for example: hydroxy, alkoxy, carboxy, cyano, halogen or nitro.
The term xe2x80x9calkoxyxe2x80x9d refers to the groups xe2x80x94O-alkyl, xe2x80x94O-alkenyl, xe2x80x94O-cycloalkyl, xe2x80x94O-cycloalkenyl, and xe2x80x94O-alkynyl. Preferred alkoxy groups are xe2x80x94O-alkyl and xe2x80x94O-alkenyl and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, 3,7-dimethyl-octa-2,6-dienyloxy and the like.
The term xe2x80x9csubstituted alkoxyxe2x80x9d refers to the groups xe2x80x94O-(substituted alkyl), xe2x80x94O-(substituted alkenyl), xe2x80x94O-(substituted cycloalkyl), xe2x80x94O-(substituted cycloalkenyl), xe2x80x94O-(substituted alkynyl) and xe2x80x94O-(optionally substituted alkylene)-alkoxy. One preferred substituted alkoxy group is xe2x80x9cpolyalkoxyxe2x80x9d or xe2x80x94O-(substituted alkylene)-alkoxy, and includes groups such as xe2x80x94OCH2OCH3, xe2x80x94OCH2CH2OCH3, and (or PEG) groups such as xe2x80x94O(CH2CH2O),CH3 and xe2x80x94O(CH2CH2O)xH where x is an integer of about 2-20, preferably about 2-10, and more preferably about 2-5.
The term xe2x80x9calkylxe2x80x9d refers to a monoradical branched or unbranched saturated hydrocarbon chain preferably having from about 1 to 20 carbon atoms, more preferably about 1 to 10 carbon atoms, and even more preferably about 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, n-decyl, tetradecyl, and the like.
The term xe2x80x9csubstituted alkylxe2x80x9d refers to an alkyl group in which 1 or more (up to about 5, preferably up to about 3) hydrogen atoms is replaced by a substituent independently selected from the group: xe2x95x90O, xe2x95x90S, acyl, acyloxy, optionally substituted alkoxy, optionally substituted amino, azido, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, heterocyclyl, carboxy, halogen, hydroxyl, nitro, cyano, sulfanyl, sulfinyl, and sulfony, or two substituents with the carbon to which they are attached may form a ring. One of the preferred optional substituents for alkyl is hydroxy, exemplified by hydroxyalkyl groups, such as 2-hydroxyethyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, and the like; dihydroxyalkyl groups (glycols), such as 2,3-dihydroxypropyl, 3,4-dihydroxybutyl, 2,4-dihydroxybutyl, and the like; and those compounds known as polyethylene glycols, polypropylene glycols and polybutylene glycols, and the like. A preferred xe2x80x9csubstituted alkylxe2x80x9d wherein the substitutents form a ring is 6-hydroxy-3-methyl-[1,3]oxazinan-6-yl.
The term xe2x80x9caminoxe2x80x9d refers to the group xe2x80x94NH2.
The term xe2x80x9csubstituted aminoxe2x80x9d refers to the group xe2x80x94NHR or xe2x80x94NRR where each R is independently selected from the group: optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted cycloalkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, acyl, optionally substituted alkoxy, carboxy and alkoxycarbonyl, and wherein RR form with the nitrogen to which they are attached a cyclic amine optionally incorporating one or more additional heteroatoms selected from O, N and S.
The term xe2x80x9carylxe2x80x9d refers to an aromatic cyclic hydrocarbon group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
The term xe2x80x9csubstituted arylxe2x80x9d refers to an aryl group as defined above, which unless otherwise constrained by the definition for the aryl substituent, is substituted with from 1 to 5 substituents, and preferably 1 to 3 substituents, independently selected from the group consisting of: xe2x95x90O, xe2x95x90S, acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl (such as tri-halomethyl), optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, azido, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydroxyl, nitro, sulfanyl, sulfinyl, and sulfonyl. Preferred aryl substituents include optionally substituted alkenyl, alkyl, alkoxy, substituted amino, halo, hydroxy, alkoxycarbonyl, carboxy, cyano, nitro, phosphoryl.
The term xe2x80x9ccarbonylxe2x80x9d refers to the di-radical xe2x80x9cxe2x80x94C(xe2x95x90O)xe2x80x94xe2x80x9d, which is also illustrated as xe2x80x9cxe2x80x94C(O)xe2x80x94xe2x80x9d.
The term xe2x80x9c(optionally substituted alkoxy)carbonylxe2x80x9d refers to the groups: xe2x80x94C(O)O-(optionally substituted alkyl), xe2x80x94C(O)O-(optionally substituted cycloalkyl), xe2x80x94C(O)O-(optionally substituted alkenyl), xe2x80x94C(O)O-(optionally substituted alkynyl), xe2x80x94C(O)O-(optionally substituted aryl), xe2x80x94C(O)O-(optionally substituted heteroaryl), and xe2x80x94C(O)O-(optionally substituted heterocyclyl). These moieties are also referred to as esters.
The term xe2x80x9c(optionally substituted amino)carbonylxe2x80x9d refers to the group xe2x80x94C(O)-(optionally substituted amino). This moiety is also referred to as a primary, secondary or tertiary carboxamide, and the xe2x80x9csubstituted aminoxe2x80x9d can be a cyclic amine.
The term xe2x80x9ccarboxyxe2x80x9d or xe2x80x9ccarboxylxe2x80x9d refers to the moiety xe2x80x9cxe2x80x94C(O)OHxe2x80x9d, which is also illustrated as xe2x80x9cxe2x80x94COOHxe2x80x9d.
The term xe2x80x9ccompound of Formula Ixe2x80x9d is intended to encompass the derivatives of the invention as disclosed, and/or the pharmaceutically acceptable salts of such compounds. In addition, the compounds employed in this invention include the individual stereochemical isomers (arising from the selection of substituent groups) and mixtures of isomers.
The term xe2x80x9ccosmeticsxe2x80x9d includes make-up, foundation, and skin care products. The term xe2x80x9cmake-upxe2x80x9d refers to products that leave color on the face, including foundations, blacks and browns, i.e., mascara, concealers, eye liners, brow colors, eye shadows, blushers, lip colors, and so forth. The term xe2x80x9cfoundationxe2x80x9d refers to liquid, creme, mousse, pancake, compact, concealer or like products that even out the overall coloring of the skin. Foundation is typically manufactured to work better over moisturized and/or oiled skin. The term xe2x80x9cskin care productsxe2x80x9d refers to products used to treat or otherwise care for, moisturize, improve, or clean the skin. Products contemplated by the phrase xe2x80x9cskin care productsxe2x80x9d include, but are not limited to, adhesives, bandages, toothpaste, anhydrous occlusive moisturizers, antiperspirants, deodorants, powder laundry detergent, fabric softener towels, occlusive drug delivery patches, nail polish, powders, tissues, wipes, solid emulsion compact, anhydrous hair conditioners medicated shampoos, scalp treatments and the like.
The term xe2x80x9cCRPxe2x80x9d or xe2x80x9cC-reactive proteinxe2x80x9d refers to a biochemical marker of inflammation. The presence of elevatel levels of CRP has been shown to be associated with various inflammatory conditions such as for example, cardiovascular diseases or disorders, including atrial fibrillation, unstable angina, coronary artery disease, peripheral artery disease, cardiac allograft vasculopathy (CAVD); mastitis; preclampsia; inflammatory bowel conditions; stroke; tissue infarction; lumbosciatic; estrogen/progestin hormone replacement therapy (HRT); infection (bacterial, viral and protozoan); bacterial meningitis; trauma; surgery; biomaterial implants; smoking; obesity; neurodegenerative diseases such as, Alzheimers; infectious disease, such as, for example, myocarditis, cardiomyopathy, acute endocarditis, pericarditis; atherosclerosis; Systemic Inflammatory Response Syndrome (SIRS)/sepsis; adult respiratory distress syndrome (ARDS); asthma; rheumatoid arthritis, osteoarthritis, systemic lupus erythematosis; Airway hyper-responsiveness (AHR); bronchial hyper-reactivity; Chronic Obstructive Pulmonary disease (COPD); Congestive Heart Failure (CHF); inflammatory complications of diabetes mellitus type I and type II; metabolic syndrome; end stage renal disease (ESRD), pre-menstrual syndrome (PMS) or muscle fatigue or inflammation; multiple organ dysfunction syndrome (MODS); airway hyper-responsiveness (AHR); bronchial hyper-reactivity; aging; acute allergic reactions; gingivitis and dermal conditions. CRP has been reported as a marker for systemic inflammation Spanheimer (2001, Postgrad. Med. 109 (4) 26) and Ridkler et al (2000, N.E.J.M. 342 (12) 83643).
The term xe2x80x9ccycloalkylxe2x80x9d refers to the monovalent saturated radical consisting of one or more rings, which can optionally be susbstituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino or sulfonyl, unless otherwise indicated. Examples of cycloalkyl radicals include but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, etc.
The term xe2x80x9cdermatologically-acceptable,xe2x80x9d as used herein, means that the compositions or components thereof so-described are suitable for use in contact with human skin without undue toxicity, incompatibility, instability, allergic response, or the like.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo.
The term xe2x80x9cheteroarylxe2x80x9d refers to an aromatic cyclic hydrocarbon group having about 1 to 40 (preferably from about 3 to 15) carbon atoms and about 1 to 10 hetero atoms (preferably about 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen) within at least one ring. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, [2,2xe2x80x2]bipyridinyl, pyrrolyl and furyl.
The terms xe2x80x9cheterocyclexe2x80x9d, xe2x80x9cheterocyclicxe2x80x9d and xe2x80x9cheterocyclylxe2x80x9d refer to a monoradical, saturated or unsaturated, non-aromatic cyclic hydrocarbon group having about 1 to 40 (preferably from about 3 to 15) carbon atoms and about 1 to 10 hetero atoms (preferably about 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen) within the ring. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morpholino, piperidinyl, 1,3-oxazinane,and the like.
The terms xe2x80x9csubstituted heterocyclexe2x80x9d, xe2x80x9csubstituted heterocyclicxe2x80x9d and xe2x80x9csubstituted heterocyclylxe2x80x9d refer to a heterocyclyl group as defined above, which unless otherwise constrained by the definition for the heterocycle, is substituted with from 1 to 5 substituents, and preferably 1 to 3 substituents, independently selected from the group consisting of: xe2x95x90O, xe2x95x90S, acyl, acyloxy, optionally substituted alkenyl, optionally substituted alkoxy, optionally substituted alkyl (such as tri-halomethyl), optionally substituted alkynyl, optionally substituted amino, optionally substituted aryl, optionally substituted aryloxy, azido, carboxyl, (optionally substituted alkoxy)carbonyl, (optionally substituted amino)carbonyl, cyano, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, halogen, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted heterocyclyl, optionally substituted heterocyclooxy, hydroxyl, nitro, sulfanyl, sulfinyl, and sulfonyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to the moiety xe2x80x9c-alkylene-heterocyclexe2x80x9d each having the meaning as defined herein.
The term xe2x80x9csubstituted heterocycloalkylxe2x80x9d refers to the moiety xe2x80x9c-(optionally substituted aklylene)-(optionally substituted heterocycle)xe2x80x9d, each having the meaning as defined herein.
The term xe2x80x9cinflammationxe2x80x9d, xe2x80x9cinflammatory conditionsxe2x80x9d, or xe2x80x9cinflammation conditionsxe2x80x9d includes but is not limited to muscle fatigue, osteoarthritis, rheumatoid arthritits, inflammatory bowel syndrome or disorder, skin inflammation, such as atopic dermatitis, contact dermatitis, allergic dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, atherosclerosis, thermal and radiation burns, acne, oily skin, wrinkles, excessive cellulite, excessive pore size, intrinsic skin aging, photo aging, photo damage, harmful UV damage, keratinization abnormalities, irritation including retinoid induced irritation, hirsutism, alopecia, dyspigmentation, inflammation due to wounds, scarring or stretch marks, loss of elasticity, skin atrophy and gingivitis.
The term xe2x80x9cischemiaxe2x80x9d refers to deficiency of blood to an organ or tissue due to functional constriction or actual obstruction of a blood vessel. Cerebral ischemia, also known as stroke, usually results from the interruption or reduction of blood and oxygen to the blood vessels of the brain; more rarely this may be the result of an hemorrhage. Signs of stroke include paralysis, slurred speech, general confusion, impairment of gait, cortical sensory loss over toes, foot and leg, and urinary incontinence, to name just a few. Many types of heart disease including cardiac arrhythmias or diseases due to cardiac structural abnormalities may produce cerebral emboli. Atrial fibrillation from any cause, including rheumatic valvular disease, may result in emboli being produced which can migrate into the arteries of the brain. Emboli formation and migration can occur as a result of arteriosclerotic cardiovascular disease and myocardial infarction. Emboli formation is also a definite risk for intracardiac surgery and prosthetic valve replacement. Heart bypass surgery and angioplasty can result in the formation of microemboli which can migrate into the arteries of the brain and cause a series of occlusions in a number of arteries, resulting in mental impairment. Cerebral embolism is also the principal complication in the transplant of artificial hearts. Furthermore, the overall risk of stroke after any type of general surgery is 0.2 to 1 percent. The vegetations of acute and subacute bacterial endocarditis can give rise to emboli which can occlude a major intracranial artery. Populations at risk of ischemia include but are not limited to patients scheduled for coronary arterial bypass graft surgery (CABG), patients at risk for postoperative complications, patients with subarachnoid hemorrhage (SAH), patients with a first or second ischemic stroke, patients with acute ischemic stroke, patients undergoing cardiopulmonary resuscitation (CPR), patients with temporary lobectomy, patients with dominant hemisphere resection, patients receiving prophylactic brain radiation, patients with closed head trauma with neurological loss, patients with microvascular multi-infarct dementia, patients with homozygous and heterozygous MELAS (Mitochondrial myopathy, encephalopathy, lactacidosis, stroke); patients with atherosclerotic or progressive supranuclear palsy disease, patients with symptomatic and asymptomatic Huntington""s disease, patients with neonatal asphyxia, patients with meningitis or encephalitis, patients with post herpetic neuropathy, patients with intermittent claudication, patients with spinal cord injury, patients with Huntington""s disease, Amyotrophic Lateral Sclerosis (ALS) or Friedreich""s ataxia, patients with diabetic neuropathy or patients with a disease associated with a hypercoagulable state secondary to systemic disease, carcinoma, vasoconstriction (including reversible cerebral vasoconstriction, e.g. migraine, trauma, idiopathy), or venous conditions (including dehydration, pulmonary embolism, pericranial infection, postpartum and postoperative states and system cancer).
The term xe2x80x9cpersonal care productsxe2x80x9d refer to health and cosmetic beauty aid products generally recognized as being formulated for beautifying and grooming the skin and hair. For example, personal care products include sunscreen products (e.g., lotions, skin creams, etc.), cosmetics, toiletries, and over-the-counter pharmaceutical products intended for topical usage.
As used herein, xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d or xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d refers to salts which retain the biological effectiveness and properties of the compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri(substituted alkenyl) amines, cycloalkyl amines, di(cycloalkyl) amines, tri(cycloalkyl) amines, substituted cycloalkyl amines, disubstituted cycloalkyl amine, trisubstituted cycloalkyl amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloalkenyl) amines, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaryl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.
The term xe2x80x9cphosphorylxe2x80x9d refers to the group xe2x80x94P(O)(ORxe2x80x3)2, where Rxe2x80x3 is independently selected from hydrogen or alkyl and aryl, which group is sometimes also referred to as xe2x80x9cphosphonoxe2x80x9d or as a xe2x80x9cphosphatexe2x80x9d or xe2x80x9cphosphonic acid.xe2x80x9d
xe2x80x9cRegulating skin conditionxe2x80x9d includes prophylactically regulating and/or therapeutically regulating skin condition, including visible and/or tactile discontinuities in skin such as, but not limited to, regulating visible and/or tactile discontinuities in the texture of skin, reducing post-inflammatory hyperpigmentation, regulating non-melanin discoloration of skin, regulating moisturization and barrier properties of skin, regulating epidermal differentiation of skin, regulating exfoliation of skin, thickening of skin to reduce skin atrophy, regulating the elasticity of skin, reducing oily skin, regulating cellulite in skin, regulating pruritus in skin, and promoting wound healing in skin. As used herein, prophylactically regulating skin condition includes delaying, minimizing and/or preventing visible and/or tactile discontinuities in skin. As used herein, therapeutically regulating skin condition includes ameliorating, e.g., diminishing, minimizing and/or effacing, discontinuities in skin. Regulating skin condition involves improving skin appearance and/or feel. Regulating skin condition includes modulation body/cranial hair growth, including retarding and/or preventing the growth of body and/or head hair. Regulating skin condition includes regulating irritation including retinoid induced irritation. As used herein regulating the skin includes the use of the compounds of the invention as bactericides, antifungal and antimicrobial agents.
xe2x80x9cRegulating the signs of skin agingxe2x80x9d includes prophylactically regulating and/or therapeutically regulating one or more of such signs (similarly, regulating a given sign of skin aging, e.g., lines, wrinkles or pores, includes prophylactically regulating and/or therapeutically regulating that sign). As used herein, prophylactically regulating such signs includes delaying, minimizing and/or preventing signs of skin aging. As used herein, therapeutically regulating such signs includes ameliorating, e.g., diminishing, minimizing and/or effacing signs of skin aging.
xe2x80x9cSigns of skin agingxe2x80x9d include, but are not limited to, all outward visibly and tactilely perceptible manifestations as well as any other macro or micro effects due to skin aging. Such signs may be induced or caused by intrinsic factors or extrinsic factors, e.g., chronological aging and/or environmental damage (e.g., sunlight, UV, smoke, ozone, pollutants, stress, etc.). These signs may result from processes which include, but are not limited to, the development of textural discontinuities such as wrinkles, including both fine superficial wrinkles and coarse deep wrinkles, skin lines, facial frown lines, expression lines, rhytides, dermatoheliosis, photodamage, premature skin aging, crevices, bumps, pits, large pores (e.g., associated with adnexal structures such as sweat gland ducts, sebaceous glands, or hair follicles), xe2x80x9corange-peelxe2x80x9d skin appearance, dryness, scaliness, flakiness and/or other forms of skin unevenness or roughness; blemishes such as acne, pimples, breakouts; excess skin oil problems such as over production of sebum, oiliness, facial shine, foundation breakthrough; abnormal desquamation (or exfoliation) or abnormal epidermal differentiation (e.g., abnormal skin turnover) such as scaliness, flakiness, keratoses, hyperkeratinization; inadequate skin moisturization (or hydration) such as caused by skin barrier damage, environmental dryness; loss of skin elasticity (loss and/or inactivation of functional skin elastin) such as elastosis, sagging (including puffiness in the eye area and jowls), loss of skin firmness, loss of skin tightness, loss of skin recoil from deformation; non-melanin skin discoloration such as undereye circles, blotching (e.g., uneven red coloration due to, e.g., rosacea), sallowness (pale color), discoloration caused by telangiectasia or spider vessels; melanin-related hyperpigmented (or unevenly pigmented) skin regions such as age spots (liver spots, brown spots) and freckles; post-inflammatory hyperpigmentation such as that which occurs following an inflammatory event (e.g., as an acne lesion, in-grown hair, insect/spider bite or sting, scratch, cut, wound, abrasion, and the like); atrophy such as, but not limited to, that associated with aging or steroid use; other histological or microscopic alterations in skin components such as ground substance (e.g., hyaluronic acid, glycosaminoglycans, etc.), collagen breakdown and structural alterations or abnormalities (e.g., changes in the stratum corneum, dermis, epidermis, the skin vascular system such as telangiectasia or spider vessels); tissue responses to insult such as itch or pruritus; and alterations to underlying tissues (e.g., subcutaneous fat, cellulite, muscles, trabeculae, septae, and the like), especially those proximate to the skin.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d refers to that amount of a compound of any of Formula I that is sufficient to effect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art.
The term xe2x80x9ctreatmentxe2x80x9d or xe2x80x9ctreatingxe2x80x9d means any treatment of a disease or disorder in a mammal, including:
preventing or protecting against the disease or disorder, that is, causing the clinical symptoms not to develop;
inhibiting the disease or disorder, that is, arresting or suppressing the development of clinical symptoms; and/or
relieving the disease or disorder that is causing the regression of clinical symptoms.
It will be understood by those skilled in the art that in human medicine, it is not always possible to distinguish between xe2x80x9cpreventingxe2x80x9d and xe2x80x9csuppressingxe2x80x9d since the ultimate inductive event or events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the event or events. Therefore, as used herein the term xe2x80x9cprophylaxisxe2x80x9d is intended as an element of xe2x80x9ctreatmentxe2x80x9d to encompass both xe2x80x9cpreventingxe2x80x9d and xe2x80x9csuppressingxe2x80x9d as defined herein. The term xe2x80x9cprotection,xe2x80x9d as used herein, is meant to include xe2x80x9cprophylaxis.xe2x80x9d
The term xe2x80x9ctopical applicationxe2x80x9d, as used herein, means to apply or spread the compositions of the present invention onto the surface of the skin.
Nomenclature
In general the nomenclature used in this Application is based on Autonom(trademark) v.2.1, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature.
The compounds of the present invention are named and numbered as described below. 
Formula Ia represents the compound according to formula I where R, R1 and R5 are hydrogen, R2 and R3 are methyl, and R4 is p-nitro-phenyl, and can be named 6,7-dimethyl-2-(4-nitro-phenyl)-benzofuran-5-ol. 
Formula Ib represents the compound according to formula I where R, R1, and R4 are hydrogen, R2 and R3 are methyl, and R5 is phenyl, and can be named 6,7-dimethyl-3-phenyl-benzofuran-5-ol.
Synthetic Reaction Parameters
The terms xe2x80x9csolventxe2x80x9d, xe2x80x9cinert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d mean a solvent inert under the conditions of the reaction being described in conjunction therewith. Solvents employed in synthesis of the compounds of the invention include, for example, methanol, acetone, water, acetonitrile, 1,4-dioxane, dimethylformamide (xe2x80x9cDMFxe2x80x9d), benzene, toluene, xylene, tetrahydrofuran (xe2x80x9cTHFxe2x80x9d), chloroform, methylene chloride (or dichloromethane, (xe2x80x9cDCMxe2x80x9d)), diethyl ether, pyridine and the like, as well as mixtures thereof. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert organic solvents.
The term xe2x80x9cq.s.xe2x80x9d means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%).
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure within a temperature range from xe2x88x9210xc2x0 C. to 110xc2x0 C. (preferably from 0xc2x0 C. to 40xc2x0 C.; most preferably at xe2x80x9croomxe2x80x9d or xe2x80x9cambientxe2x80x9d temperature, e.g., 20xc2x0 C.). Further, unless otherwise specified, the reaction times and conditions are intended to be approximate, e.g., taking place at about atmospheric pressure within a temperature range of about xe2x88x9210xc2x0 C. to about 110xc2x0 C. (preferably from about 0xc2x0 C. to about 40xc2x0 C.; most preferably at about xe2x80x9croomxe2x80x9d or xe2x80x9cambientxe2x80x9d temperature, e.g., approximately 20xc2x0 C.) over a period of about 1 to about 10 hours (preferably about 5 hours). Parameters given in the Examples are intended to be specific, not approximate.
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can, of course, also be used.
Starting Materials
The starting compounds, e.g., 2,3-dimethylhydroquinone, are commercially available, e.g. from Aldrich Chemical Company, Milwaukee, Wis., or may be readily prepared by those skilled in the art using commonly employed methodology. 
Referring to Reaction Scheme 1, a 2,3-substituted hydroquinone of Formula 101 is treated with one equivalent of a 2-halo-1-substituted-ethanone, preferably 2-bromo-1-substituted-ethanone, most preferably 2-bromo-1-substituted phenyl ethanone, in the presence of a base such as sodium carbonate, potassium carbonate or cesium carbonate in a solvent such as acetone, THF, or DMF, to give 2-(4-hydroxy-2,3-substituted-phenoxy)-1-substituted-ethanone of Formula 102. Compound of Formula 102 can subsequently be treated with an acid such as polyphosphoric acid, hydrochloric acid, or sulfuric acid in an inert solvent such as toluene or xylene, to cyclise into a benzofuran compound of Formula 103.
Similarly treating a 2,3-substituted hydroquinone of Formula 102 with 2 or more equivalents of a 2-halo-1-substituted ethanone in the presence of a base, followed by cyclization in the presence of an acid, can give a compound of Formula 105. 
Referring to Scheme 2, a compound of Formula 201 wherein xe2x80x9cProtxe2x80x9d is a hydroxy protecting group, preferably a tetrahydropyranyl group, when reacted with a 2-halo-1-substituted ethanone, preferably a 2-bromo-1-substituted ethanone in the presence of a base such as sodium carbonate, potassium carbonate, or cesium carbonate in a solvent such as acetone, THF, or DMF, followed by cyclization in the presence of an acid as described in reaction scheme 1, can give a compound of Formula 202.
The following combinations and permutations of substituent groups (sub-grouped, respectively, in increasing order of preference) define compounds that are preferred as compositions of matter and compounds for use in the methods and pharmaceutical and cosmetic compositions according to the invention.
The compounds of any of Formula I where R2 and R3 are optionally substituted alkyl, particularly those wherein R2 and R3 are methyl.
Preferably those where R1 is hydrogen or halogen
Especially those where R is hydrogen.
The compounds of any of Formula I where R1 is hydrogen or halo
Preferably those where RX is hydrogen
The compounds of any of Formula I where R is hydrogen, alkyl, acyl, phosphoryl or polyalkoxy, preferably hydrogen, and R1 is hydrogen
1. Particularly those wherein R2 and R3 are methyl
Especially those of Formula I where R5 is optionally substituted aryl, wherein the substitutents are chosen from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano
Particularly those where R5 is optionally substituted phenyl.
Particularly those where R5 is optionally substituted phenyl and R4 is hydrogen.
Especially those of Formula I where R4 is optionally substituted aryl
Particularly those where R4 is optionally substituted phenyl
Preferably those where R4 is para-substituted phenyl, wherein the substitutents are chosen from alkyl, alkoxy, hydroxy, (optionally substituted alkoxy)carbonyl, nitro, halo, and cyano
Preferably those where R4 is 4-nitrophenyl, 4-cyanophenyl and R5 is hydrogen.
Especially those of Formula I where R4 is formyl, (optionally substituted alkyl)carbonyl, (optionally substituted aryl)carbonyl, (optionally substituted heterocyclyl)carbonyl, (optionally substituted heterocyclylalkyl)carbonyl
Particularly those where R4 is (optionally substituted aryl)carbonyl
Particularlyl those where R4 is (optionally substituted alkyl)carbonyl
Particularly those where R4 is alkylcarbonyl optionally substituted with halogen, hydroxy or heterocyclyl, especially substituted with morpholin-1-yl
Particularly those where R4 is formyl
Preferably those where R4 is selected from formyl, phenylcarbonyl, bromoacetyl, morpholin-1-yl-acetyl, and acetyl; and R5 is hydrogen
Especially those wherein R4 is (optionally substituted alkoxy)carbonyl, (optionally substituted alkenyloxy)carbonyl, (optionally substituted amino)carbonyl, carboxy, or hydroxy(optionally substituted)alkyl;
Particularly those where R4 is (optionally substituted alkoxy)carbonyl, preferably those where the alkoxy is polyalkoxy, or (optionally substituted alkenyloxy) carbonyl, preferably those where the alkenyloxy is geranyloxy.
Particularly those where R4 is (optionally substituted amino)carbonyl, preferably those wherein the amino is substituted with optionally substituted alkyl, especially hydroxyalkyi, or wherein the amino is a cyclic amine.
Preferably those where R4is morpholin-1-yl-carbonyl; bis-(2-hydroxy-ethyl)-amide, 2-hydroxy-ethyl-amide, carboxylic acid; carboxylic acid methyl ester; carboxylic acid 3,7-dimethyl-octa-2,6-dienyl ester; [2-(2-methoxy-ethoxy)-ethoxy]ethyl ester; and R5 is hydrogen.
Especially those where R4 are hydroxy (optionally substituted) alkyl
Particularly where R4 is hydroxymethyl, 1-hydroxy-2-morpholiny4-yl ethyl or 6-hydroxy-3-methyl-[1,3]oxazinan-6-yl.
The compounds of any of Formula I wherein R and R1 with the atoms to which they are attached form an optionally substituted ring
Especially those wherein R and R1 with the atoms to which they are attached form a furan ring substituted with an unsubstituted phenyl ring or with a substituted phenyl ring, wherein one or more substituents are independently selected from alkyl, alkenyl, halo alkyl, hydroxy, alkoxy, carboxy, ester, haloalkyl, and halo.
The compounds preferred for use in the invention include the following, as well as their stereoisomers, salts, and mixtures thereof (as appropriate):
(5-Hydroxy-3,6,7-trimethyl-benzofuran-2-yl)-phenyl-methanone;
(5-Hydroxy-6,7-dimethyl-benzofuran-2-yl)-morpholin-4-yl-methanone;
1-(5-Hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone;
Acetic acid 2-(2-bromo-acetyl)-6,7-dimethyl-benzofuran-5-yl ester;
2-(1-Hydroxy-2-morpholin4-yl-ethyl)-6,7-dimethyl-benzofuran-5-ol;
Acetic acid 6,7-dimethyl-2-(2-morpholiin-1-yl-acetyl)-benzofuran-5-yl ester;
Acetic acid 2-(6-hydroxy-3-methyl-[1,3]oxazinan-6-yl)-6,7-dimethyl-benzofuran-5-yl ester;
1-(5-Hydroxy-6,7-dimethyl-benzofuran-2-yl)-2-morpholin-4-yl-ethanone;
1-(4-Bromo-5-hydroxy-6,7-dimethyl-benzofuran-2-yl)-ethanone;
2-Hydroxymethyl-6,7-dimethyl-benzofuran-5-ol;
6,7-Dimethyl-3-phenyl-benzofuran-5-ol;
6,7-Dimethyl-2-(4-nitro-phenyl)-benzofuran-5-ol;
5-Hydroxy-6,7-dimethyl-benzofuran-2-carbaldehyde;
4-(5-Hydroxy-6,7-dimethyl-benzofuran-2-yl)-benzonitrile;
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid;
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid methyl ester;
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid 3,7-dimethyl-octa-2,6-dienyl ester;
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid bis-(2-hydroxy-ethyl)-amide;
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl ester;
5-Hydroxy-6,7-dimethyl-benzofuran-2-carboxylic acid (2-hydroxy-ethyl)-amide;
3-(4-Methoxy-phenyl)-6,7-dimethyl-benzofuran-5-ol;
3-(4-Chloro-phenyl)-6,7-dimethyl-benzofuran-5-ol;
3-(4-Fluoro-phenyl)-6,7-dimethyl-benzofuran-5-ol;
4,5-Dimethyl-1,8-diphenyl-benzo[1,2-b;4,3-bxe2x80x2]difuran;
1,8-Bis-(4-fluoro-phenyl)-4,5-dimethyl-benzo[1,2-b;4,3-bxe2x80x2]difuran; and
1,8-Bis-(4-methoxy-phenyl)-4,5-dimethyl-benzo[1,2-b;4,3-bxe2x80x2]difuran.
General Utility
Compounds, compositions/formulations and methods of the present invention are useful in treating a number of disorders, particularly those characterized by oxidative stress and/or inflammation. In particular, compounds of the present invention can be used in the treatment of cerebral ischemia (xe2x80x9cstrokexe2x80x9d), myocardial ischemia (myocardial infarction and other forms of heart disease), diabetes, renal disease, pre-menstrual syndrome, asthma, cardiopulmonary inflammatory disorders, chronic heart failure, rheumatoid arthritis, muscle fatigue, intermittent claudication and for the preservation of allograft tissue for transplantation.
The compounds of the present invention have also shown use in reducing C-reactive protein (CRP) associated with inflammation and /or inflammatory conditions including cardiovascular diseases or disorders, such as atrial fibrillation, unstable angina, coronary artery disease, peripheral artery disease, cardiac allograft vasculopathy (CAVD), mastitits, preclampisia, inflammatory bowel conditions, stroke, tissue infarction, lumbosciatic, estrogen/progestin hormone replacement therapy (HRT); infection (bacterial, viral and protozoan), bacterial meningitis, trauma, surgery, biomaterial implants, smoking, obesity, neurodegenerative diseases such as Alzheimers, infectious disease such as for example myocarditis, cardio rhyopathy, acute endocarditis orpericarditis, aatherosclerosis, sustemic inflammatory response (SIRS)/sepsis, adult respirtoru distress syndrome (ARDS), asthma, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosis, airway hyperresponsiveness (AHR), bronchial hyper-reactivity, chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), inflammatory complications of diapetes mellitus type I and II, metabolic syndrome, end stage reanl disease (ESRD), pre-menstrual syndrome (PMS) or muscle fatigue or inflammation, multiple organ dysfunction syndrome (MODS), airway hyper-responsiveness (AHR), bronchia hyper-reactivity, aging, acute allergic reactions, periodontal disease, such as gingivitis and dermal conditions including inflammatory skin conditions.
The compounds, formulations and methods of the present invention are useful in treating a number of dermatological conditions, including, but not limited to prevention and protecting skin tissue against age-related damage or damage resulting from insults such as harmful ultraviolet (UV) radiation, stress and fatigue. Such compounds, formulations and methods are likewise useful in hair care and treatments of the scalp, for example by incorporation in medicated shampoos, anhydrous hair conditioners and the like. Such compounds, formulations and methods are likewise useful in reduction of hair growth.
For example, exposure to sunlight can pose a number of hazards to the skin. The major short-term hazard of prolonged exposure to sunlight is erythema, i.e., sunburn, which primarily results from UVB radiation having a wavelength of from about 290 nm to about 320 nm. Over the long term, however, such prolonged exposure can often cause malignant changes in the skin surface to occur. Epidemiologic studies demonstrate a strong relationship between sunlight exposure and human skin cancer. Another long-term hazard of ultraviolet radiation is premature aging of the skin, which is primarily caused by UVA radiation having a wavelength of from about 320 nm to about 400 nm. This condition is characterized by wrinkling and pigment changes of the skin, along with other physical changes such as cracking, telangiectasis, solar dermatoses, ecchymoses, and loss of elasticity. Individuals, particularly those having light-skin who burn easily and tan poorly, who have had a great deal sun exposure in childhood can show the following gross cutaneous alterations in later adult life: wrinkling, leatheriness, yellowing, looseness, roughness, dryness, mottling (hyperpigmentation) and various premalignant growths (often subclinical). These cumulative effects of sunlight are often referred to as xe2x80x9cphotoagingxe2x80x9d. Although the anatomical degradation of the skin is most advanced in the elderly, the destructive effects of excessive sun exposure are already evident by the second decade. Serious microscopic alterations of the epidermis and dermis occur decades before these become clinically visible. Wrinkling, yellowing, leatheriness and loss of elasticity are very late changes.
The compositions of the present invention are useful for regulating body and/or head hair growth, particularly for the reduction of hair growth. The composition should be applied to the area of the body where it is desired to inhibit hair growth. Typically, the composition can be applied to the face, particularly to the beard area of the face, i.e., the cheek, neck, upper lip, and chin. The composition can also be applied to the legs, arms, torso and armpit. The compostion is particularly suitable for the treatment of hirsutism. In humans the composition should be applied onece or twice a day, or even more frequently, for at least three months to achieve a perceived reduction in hair growth.
Other skin conditions that may benefit from the methods of the present invention include, but are not limited to, diaper rash, a common form of contact dermatitis and irritation occurring in infants, as well as adults, who wear diapers. U.S. Pat. No. 6,211,186, incorporated herein by reference, describes possible etiologies and methods of treating this condition. It is generally thought that one or more fecal and lipolytic enzymes, as well as ammonia, bacteria, urine pH, overhydration and Candida albicans may be involved in the onset of skin irritation and inflammation associated with diaper rash. It is also likely that physiological responses of the skin to the irritants, such as production of cytokines by keratinocytes, contribute to the ensuing appearance of erythema, papules, scaling and ulceration characteristic of the condition. In addition, compositions and methods of the present invention may be useful in treating acne, a skin condition characterized by a profound inflammatory component, and irritation including retinoid iinduced irritation.
The compositions of the present invention are also useful for regulating skin condition, including visible and/or tactile discontinuities in skin (especially the skin surface; such discontinuities are generally undesired). Such discontinuities may be induced or caused by internal and/or external factors, and include the signs of skin aging described herein. Visible discontinuities include pigmentation disorders.
The compositions of the present invention are useful for regulating signs of skin aging, especially visible and/or tactile discontinuities in skin texture associated with aging. It is to be understood that the present invention is not to be limited to regulation of the xe2x80x9csigns of skin agingxe2x80x9d that arise due to the above-mentioned mechanisms associated with skin aging, but is intended to include regulation of such signs irrespective of their mechanism of origin.
Testing
This section describes how compositions incorporating compositions of the present invention are selected, using in vitro and/or in vivo animal models, for example, and used as therapeutic interventions in three exemplary indications, i.e., stroke, chronic heart failure and myocardial infarction.
Insults to the brain that disrupt its blood supply, as in ischemia, or its oxygen supply, as in hypoxia (low oxygen) or anoxia (no oxygen), rapidly cause neuronal imbalance leading to cell death (Flynn, C. J., et al., 1989, in G. Siegel et al., (Eds), Basic Neurochemistry, Raven Press, N.Y.). Investigations into the cellular and molecular mechanisms that lead to neuronal damage and inflammation associated with various types of brain ischemia can be carried out using in vitro model systems, such as primary cell cultures, that retain the metabolic characteristics of neurons in vivo. The use of such cell-based models has led to advances in identification of biochemical mechanisms leading to neuronal death in conditions such as anoxia, hypoglycemia, excitotoxicity, and exposure to reactive oxygen species. Neuronal cell lines such as the pheochromocytoma cell line, PC12, are also useful models for studying the effects of oxidative stress on the structure and function of neuron-specific proteins that are expressed in the cell lines. As many neuronal cell lines do not express all the properties of genuine neurons, primary neuronal cultures are now widely used as in vitro models in which to discern the processes that occur in intact brain.
In vitro models of ischemia approximate oxygen and glucose deprivation that mimic in vivo conditions, for example, by placing neuronal cultures into large anaerobic or hypoxic chambers and exchanging culture medium with de-oxygenated and defined ionic composition media. The toxic overstimulation of neuronal glutamcate receptors, especially N-methyl-D-aspartate (NMDA) receptors, contributes to hypoxic-ischemic neuronal injury (Choi, D. M., 1988, Neuron 1: 623-634), ischemic induction of reactive oxygen species (ROS) (Watson, B. D., et al.,1988, Ann NY Acad Sci., 59: 269-281), excessive calcium influx (Grotta, J. C., 1988, Stroke 19: 447454), arachidonic acid increase (Siesjo, B. K., 1981, J. Cereb. Blood Flow Metab. 1: 155-186) and DNA damage (MacManus, J. P., et al., 1993, Neurosci. Lett., 164: 89-92), each causing a cascade of neurodegeneration.
Primary embryonic hippocampal neuronal cells are widely recognized as useful in models of neuronal function. The hippocampus is a source of a relatively homogenous population of neurons with well-characterized properties typical of central nervous system (CNS) neurons in general. Pyramidal neurons, the principal cell type in the hippocampus, have been estimated to account for 85% to 90% of the total neuronal population (Banker and Goslin, 1998, Culturing Nerve Cells, 2nd edition. The MIT Press, Cambridge, Mass.). The hippocampus also exhibits a remarkable capacity for activity-dependent changes in synaptic function, such as long-term potentiation (Hawkins R D, Kandel E R, Siegelbaum S A. (1993) Learning to modulate transmitter release: themes and variations in synaptic plasticity [review], Ann. Rev Neurosci. 16:625-665.).
In experiments carried out in support of the present invention according to methods detailed in the Examples, anoxia/ischemia was induced in primary cultures of hippocampal neuronal cells, and compounds were tested for their ability to prevent cell death. Compounds found to have activity in such in vitro assays are then further tested in one or more animal models of cerebral ischemia (xe2x80x9cstrokexe2x80x9d), such as the middle cerebral artery occlusion (MCAO) model in rats.
Briefly, primary cultures of hippocampal neurons are used to test compounds for activity in neuronal protection. Hippocampal cultures are typically prepared from 18- to 19-day fetal rats. At this age, the generation of pyramidal neurons, which begins in the rat at about E15, is essentially complete. The brain tissue at this stage is relatively easy to dissociate, the meninges are removed readily, and the number of glial cells still is relatively modest (Park L C, Calingasan N.Y., Uchida K, Zhang H, Gibson G E. (2000) Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in culture. J Neurochem 74(1):1 14-124).
In order to evaluate the activity of compounds of the present invention, a test compound is assessed for its ability to protect cells against one or more standard stressors, including hypoxia, as detailed in the Examples. In general, desirable therapeutic compound candidates are effective in this model at concentrations less than about 1 mM and even more preferably, less than about 100 xcexcM. By effective, it is meant that such compounds protect at least 20%, preferably 30%, more preferably 40% and even more preferably 50% or more of the cells tested from stressor-induced death. By way of example, compounds that are effective in providing protection over a concentration a range of about 1 to 1000 xcexcM would be expected to provide neuroprotection in vivo. Since precise values may vary depending upon the specific conditions under which the neuroprotective cell assay is carried out, it is the intent of the present disclosure to provide the foregoing criteria as guidance in the form of a benchmark against which to compare subsequently tested compounds, rather than to provide absolute concentrations at which the compounds of the present invention are considered to be effective. Typically, compounds that are found to be neuroprotective in such in vitro cell systems are then further tested in an in vivo animal model of neuroprotection, such as the rat middle cerebral artery occlusion model described below, or other appropriate models such as are well known in the art.
Cerebral ischemic insults are modeled in animals by occluding vessels to, or within, the cranium (Molinari, G. F., 1986, in H.J.M. Barnett, et al., (Eds) Stroke: Pathophysiology, Diagnosis and Management, Vol. 1, Churchill Livingstone, NY). The rat middle cerebral artery occlusion (MCAO) model is one of the most widely used techniques to induce transient focal cerebral ischemia approximating cerebral ischemic damage in humans, e.g., those who suffer from a stroke. The middle cerebral artery used as the ischemic trigger in this model is the most affected vessel in human stroke. The model also entails a period of reperfusion, which typically occurs in human stroke victims. MCAO involving a two-hour occlusion has been found to produce the maximum size of cortical infarction obtainable without increased mortality at twenty-four hours.
Briefly, a nylon filament is implanted into the right carotid artery of the rat. To effect occlusion, the rat is anesthetized, and the filament is advanced into the internal carotid artery 18-20 mm from the point of bifurcation of internal and external arteries and a suture is tightly ligated around the filament for a period of two hours. Two hours post occlusion, animals are re-anesthetized, and the filament is removed, to allow reperfusion for the remainder of the experiment. Test drugs can be administered any time during this processxe2x80x94before, during or after occlusion, and can be administered by one or more of a variety of means, including but not limited to intracerebroventricular (ICV) infusion, intravenous (IV) infusion, intraperitoneal (IP) administration, as well as enteral administration (e.g., gavage). Animals are maintained normothermic during the experiment, as described in the Examples. At a pre-determined time following occlusion and reperfusion, animals are sacrificed and their brains are removed and processed for assessment of damage as measured by infarct volume. In general, compounds are considered to have activity in this model, if they provide a significant reduction in total infarct volume at a dose that is less than about 10 mg/kg, preferably less than 1 mg/kg, more preferably less than 100 xcexcg/kg and even more preferably less than about 1 xcexcg/kg, when administered ICV or IV. By significant reduction of total infarct volume is meant a reduction of at least 20%, preferably at least 30%, more preferably at least 40%, and even more preferably about 50%, compared to control values.
Further validation of efficacy in neuroprotection can be assessed in functional tests, such as the grip strength test or the rotorod test. Animals treated with compounds that show neuroprotection maintain their pre-MCAO grip strength values after MCAO, as compared to untreated animals, who showed a significant reduction in grip strength, indicating loss of sensorimotor function. Likewise, animals treated with compounds that show neuroprotection also maintained their pre-MCAO rotorod activity scores after MCAO, as compared to untreated animals, who showed a significant reduction in rotorod scores, indicating loss of sensorimotor function at higher brain levels.
Similarly, primary cultures of myocytes can be used to test compounds in vitro for ability to provide protection against heart damage, resulting for example from myocardial ischemia or congestive heart failure. Preparation of myocardiocytes from neonatal rats is described in the Examples. Such cells are typically used to study molecular models of myocardial ischemia (Webster, K A, Discher, D J and Bishopric, N H. 1995. J. Mol. Cell Cardiol. 27:453458; Camilleri, L, Moins, N, Papon, J, Maublant, J, Bailly, P, de Riberolles, C and Veyre, A. 1997. Cell Biol. and Toxicol. 13:435-444; Bielawska, A E, Shapiro, J P, Jiang, L, Melkonyan, H S, Piot, C, Wolfe, C L, Tomei, L D, Hannun, Y A and Umansky, S R. 1997. Am. J. Pathol. 151:1257-1263) and are therefore accepted as indicative of myoprotective activity. Exemplary stressor assays for this purpose are provided in the Examples. For example, cardiomyocytes in culture exhibit contractile (xe2x80x9cbeatingxe2x80x9d) activity; each cardiomyocyte contraction is associated with a rise in intracellular calcium termed a xe2x80x9ccalcium transientxe2x80x9d. These calcium transients can be measured using Fluo-4, a fluorescent dye which exhibits large fluorescence intensity increases upon the binding of calcium. This assay is cell-based and tests the ability of potential cytoprotectant molecules to guard against ischemic damage and allow the cells to maintain their contractile function.
Further validation of compounds can be carried out in a whole organ assay, such as the isolated heart (Langendorff) model of cardiac function. Similarly, compounds can be further validated in additional animal models of disease (e.g., diabetes, renal failure, asthma, muscle fatigue, inflammation), such as are well known in the art.
This section describes how compositions incorporating compositions of the present invention are selected, using in vitro and in vivo animal models and used as therapeutic interventions in dermatological indications. A number of cell screening assays for mediators of inflammatory response are well known in the art. Such mediators include but are not limited to inflammatory cytokines, interleukin -1.beta., and tumor necrosis factor alpha (TNF.alpha.). Other molecules have been reported for use as markers of inflammation, including for example C-reactive protein (CRP), certain adhesion molecules, and proteins such as leukotriene, thromboxane and isoprostane.
In vitro evaluation of anti-inflammatory activity can be determined by well characterized assays such as the E-selectin (ELAM) production assay or the CRP assay exemplified in Example 9, and in vivo evaluation can be determined by the carrageenan-induced paw edema assay. The ELAM assay measures activity of test compounds in reducing espression of ELAM in acrivated endothelial cells. Briefly, endothelial cells are crivated by adding known acrivalors such as lipopolysaccharides, TNF, or IL-1.beta., alone or in some combination. Activated cells produce ELAM, which can be measure unsing, for example, an E-selectin monoclonal antibody-based ELISA assay. In studies carried out in support of the present invention, ELAM production was decreased. In vivo evaluation of anti-inflammatory activity as described in Example 10, can be determined by well characterized assay. (Gabor, M. Mouse Ear Inflammation Models and their Pharmacological Appications, 2000). Carrageenan-Induced Paw Edema is a model of inflammation, which causes time-dependent edema formation following carrageenan administration into the intraplantar survace of a rat paw. The application of arachidonic acid (AA) to the ears of mice produces immediate vasodilatation and erythema, followed by the abrupt development of edema, which is maximal at 40 to 60 min. The onset of edema coincides with the extravasations of protein and leukocytes. After one hour the edema wanes rapidly and the inflammatory cells leave the tissue so that at 6 hours the ears have returned to near normal. These assays, respectively, measure a test compounds ability to treat these inflammatory processes via systemic and topical routes of administration.
Cytoprotective activity for skin can be evaluated in cell culture using the Epiderm Skin Model (EPI-100) from the Mattek Corporation of Ashland, Mass., as dexcribed in Example 7. Cell cultures of neonatal foreskin are cultured in accordance with the manufacturer""s directions, and are assayed for percent cellular viability by measuring the amount of 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) dye taken up by the cells.
Activity with respect to hair growth inhibition is described in Example 8.
Administration
The compounds of Formula I are administered at a therapeutically effective dosage, e.g., a dosage sufficient to provide treatment for the disease states previously described. Administration of the compounds of the invention or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities.
While human dosage levels have yet to be optimized for the compounds of the invention, generally, a daily dose is from about 0.01 to 2.0 mg/kg of body weight, preferably about 0.1 to 1.5 mg/kg of body weight, and most preferably about 0.3 to 1.0 mg/kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be about 0.7 to 140 mg per day, preferably about 7.0 to 105 mg per day, and most preferably about 21 to 70 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.
The compositions of the present invention are suitable for providing protection against the harmful effects of ultraviolet radiation, preferably in personal care products. More preferably, the compositions of the present invention are suitable for use as sunscreens to provide protection to human skin from the harmful effects of UV radiation, which include, but are not limited to, sunburn and premature aging of the skin. The present invention therefore also further relates to methods of protecting human skin from the harmful effects of UV radiation. Such methods generally involve attenuating or reducing the amount of UV radiation that reaches the skin""s surface. In the case of the present invention, the methods of treatment for the harmful effects of ultraviolet radiation also include administration of a composition of the invention after the exposure to UV radiation has already taken place. To protect the skin from UV radiation, a safe and effective (photoprotective) amount of the composition is topically applied to the skin. xe2x80x9cTopical applicationxe2x80x9d refers to application of the present compositions by spreading, spraying, etc. onto the surface of the skin. The exact amount applied may vary depending on the level of UV protection desired. From about 0.5 mg of composition per square centimeter of skin to about 25 mg of composition per square centimeter of skin are typically applied.
Compounds and methods of the invention may be employed in any skin care application where decreased inflammatory response is desirable. For example, compounds and compositions of the invention may be incorporated into leave-on and rinse-off acne preparations, facial milks and conditioners, shower gels, foaming and non-foaming facial cleansers, cosmetics, hand and body lotions, leave-on moisturizers, cosmetic and cleaning wipes, salves for poison ivy, chicken pox, or pruritis, or the like. Generally, for dermal applications, topical administration is preferred; however, systemic administration, as described elsewhere herein, is also possible.
Compositions of the present invention may also be used in cosmetic compositions. Cosmetic compositions of the present invention are ideally suited for use in treating the skin and lips, especially in the form of a lipstick or lip balm for applying to the lips a permanent or semi-permanent color, ideally with a gloss or luster finish. The cosmetic compositions can also be used in treating the skin and/or lips with a skin care agent for protection against exposure to adverse weather, including the wind and rain, dry and/or hot environments, environmental pollutants (e.g., ozone, smoke, and the like), or exposure to excessive doses of sunlight. The compositions are also useful in providing sun protection, moisturizing and/or conditioning for the hair and skin, improved skin feel, regulating skin texture, reducing fine lines and wrinkles, reducing oily shine on hair or skin, skin lightening and reducing skin or hair odor.
The cosmetic compositions can accordingly be applied to the skin and/or lips in the traditional manner with or without a conventional holder or applicator to provide a decorative and/or protective film thereto.
In employing the compounds of this invention for treatment of the above conditions, any pharmaceutically acceptable mode of administration can be used. The compounds of formula I can be administered either alone or in combination with other pharmaceutically acceptable excipients, including solid, semi-solid, liquid or aerosol dosage forms, such as, for example, tablets, capsules, powders, liquids, suspensions, suppositories, aerosols or the like. The compounds of formula I can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for the prolonged administration of the compound at a predetermined rate, preferably in unit dosage forms suitable for single administration of precise dosages. The compositions will typically include a conventional pharmaceutical carrier or excipient and a compound of formula I or a pharmaceutically acceptable salt thereof. In addition, these compositions may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, and the like, including, but not limited to anticoagulants, blood clot dissolvers, permeability enhancers and slow release formulations.
Generally, depending on the intended mode of administration, the pharmaceutically acceptable composition will contain about 0.1% to 90%, preferably about 0.5% to 50%, by weight of a compound or salt of formula I, the remainder being suitable pharmaceutical excipients, carriers, etc.
One preferred manner of administration for the conditions detailed above is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. For such oral administration, a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, dispersible tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably the compositions will take the form of a pill or tablet and thus the composition will contain, along with the active ingredient, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose and derivatives thereof, and the like.
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc. an active compound as defined above and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension. If desired, the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, or solubilizing agents, pH buffering agents and the like, for example, sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Penn., 15th Edition, 1975. The composition or formulation to be administered will, in any event, contain a quantity of the active compound in an amount effective to alleviate the symptoms of the subject being treated.
Dosage forms or compositions containing active ingredient in the range of 0.005% to 95% with the balance made up from non-toxic carrier may be prepared.
For oral administration, a pharmaceutically acceptable non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, talcum, cellulose derivatives, sodium crosscarmellose, glucose, sucrose, magnesium carbonate, sodium saccharin, talcum and the like. Such compositions take the form of solutions, suspensions, tablets, capsules, powders, sustained release formulations and the like. Such compositions may contain 0.01%-95% active ingredient, preferably 0.1-50%.
For a solid dosage form, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. Such diester solutions, and the preparation and encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245; 4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g. in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration.
Alternatively, liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
Other useful formulations include those set forth in U.S. Pat. No. Re. 28,819 and U.S. Pat. No. 4,358,603.
The formulation can be administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad libitum when relief of symptoms is specifically required. For example, the formulation may be administered as a bolus or as a continuous intravenous infusion after onset of symptoms of stroke, myocardial infarction or chronic heart failure.
Parenteral administration is generally characterized by injection, either subcutaneously, intramuscularly or intravenously. Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like. In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents, solubility enhancers, and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, cyclodextrins, etc:
A more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Pat. No. 3,710,795. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the compound and the needs of the subject. However, percentages of active ingredient of 0.01% to 10% in solution are employable, and will be higher if the composition is a solid which will be subsequently diluted to the above percentages. Preferably the composition will comprise 0.2-2% of the active agent in solution.
Nasal solutions of the active compound alone or in combination with other pharmaceutically acceptable excipients can also be administered.
Formulations of the active compound or a salt may also be administered to the respiratory tract as an aerosol or solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose. In such a case, the particles of the formulation have diameters of less than 50 microns, preferably less than 10 microns.
Dermatologic formulations of the present invention typically comprise a cytoprotective derivative of any of Formula I and optionally, a polar solvent. Solvents suitable for use in the formulations of the present invention include any polar solvent capable of dissolving the cytoprotective derivative. Suitable polar solvents include: water; alcohols (such as ethanol, propyl alcohol, isopropyl alcohol, hexanol, and benzyl alcohol); polyols (such as propylene glycol, polypropylene glycol, butylene glycol, hexylene glycol, maltitol, sorbitol, and glycerine); and panthenol dissolved in glycerine, flavor oils and mixtures thereof. Mixtures of these solvents can also be used. Exemplary polar solvents are polyhydric alcohols and water. Examples of preferred solvents include glycerine, panthenol in glycerine, glycols such as propylene glycol and butylene glycol, polyethylene glycols, water and mixtures thereof. Additional preferred polar solvents for use are alcohols, glycerine, panthenol, propylene glycol, butylene glycol, hexylene glycol and mixtures thereof.
Typically, the formulations of the present invention will comprise from about 0.1% to about 80%, preferably from about 0.5% to about 60%, more preferably from about 1% to about 30% and most preferably from about 3% to about 18% polar solvent.
An emollient may also be added to the cosmetic/dermatological compositions of the present invention. The emollient component can comprise fats, oils, fatty alcohols, fatty acids and esters which aid application and adhesion, yield gloss and most importantly provide occlusive moisturization. Suitable emollients for use are isostearic acid derivatives, isopropyl palmitate, lanolin oil, diisopropyl dimerate, maleated soybean oil, octyl palmitate, isopropyl isostearate, cetyl lactate, cetyl ricinoleate, tocopheryl acetate, acetylated lanolin alcohol, cetyl acetate, phenyl trimethicone, glyceryl oleate, tocopheryl linoleate, wheat germ glycerides, arachidyl propionate, myristyl lactate, decyl oleate, propylene glycol ricinoleate, isopropyl lanolate, pentaerythrityl tetrastearate, neopentylglycol dicaprylate/dicaprate, hydrogenated coco-glycerides, isononyl isononanoate, isotridecyl isononanoate, myristal myristate, triisocetyl citrate, cetyl alcohol, octyl dodecanol, oleyl alcohol, panthenol, lanolin alcohol, linoleic acid, linolenic acid, sucrose esters of fatty acids, octyl hydroxystearate and mixtures thereof. Examples of other suitable emollients can be found in the Cosmetic Bench Reference, pp. 1.19-1.22 (1996), incorporated herein by reference. Suitable emollients include polar emollient emulsifiers (such as linear or branched chained polyglycerol esters) and non-polar emollients. The emollient component typically comprises from about 1% to about 90%, preferably from about 10% to about 80%, more preferably from about 20% to about 70%, and most preferably from about 40% to about 60%, of the cosmetic composition.
By xe2x80x9cpolar emollient,xe2x80x9d as used herein, is meant any emollient emulsifier having at least one polar moiety and wherein the solubility (at 30 degrees C.) of the cytoprotective derivative compound in the polar emollient is greater than about 1.5%, preferably greater than about 2%, more preferably greater than about 3%. Suitable polar emollients include, but are not limited to, polyol ester and polyol ethers such as linear or branched chained polyglycerol esters and polyglycerol ethers. Nonlimiting examples of such emollients include PG3 diisosterate, polyglyceryl-2-sesquiisostearate, polyglyceryl-5-distearate, polyglyceryl-10-distearate, polyglyceryl-10-diisostearate, acetylated monoglycerides, glycerol esters, glycerol tricaprylate/caprate, glyceryl ricinoleate, glyceryl isostearate, glyceryl myristate, glyceryl linoleate, polyalkylene glycols such as PEG 600, monoglycerides, 2-monolaurin, sorbitan esters and mixtures thereof.
By xe2x80x9cnon-polar emollient,xe2x80x9d as used herein, means any emollient emulsifier possessing no permanent electric moments. Suitable non-polar emollients include, but are not limited to, esters and linear or branched chained hydrocarbons. Non-limiting examples of such emollients isononyl isononanoate, isopropyl isostearate, octyl hydroxystearate, diisopropyl dimerate, lanolin oil, octyl palmitate, isopropyl palmitate, pariffins, isoparrifins, acetylated lanolin, sucrose fatty acid esters, isopropyl myristate, isopropyl stearate, mineral oil, silicone oils, dimethicone, allantoin, isohexadecane, isododecane, petrolatum, and mixtures thereof. The solubility of the compound in polar or non-polar emollients is determined according to methods known in the art.
Suitable oils include esters, triglycerides, hydrocarbons and silicones. These can be a single material or a mixture of one or more materials. They will normally comprise from 0% to about 100%, preferably from about 5% to about 90%, and most preferably from about 70% to about 90% of the emollient component.
Oils that act as emollients also impart viscosity, tackiness, and drag properties to cosmetic compositions such as lipstick. Examples of suitable oils include caprylic triglycerides; capric triglyceride; isostearic triglyceride; adipic triglyceride; propylene glycol myristyl acetate; lanolin; lanolin oil; polybutene; isopropyl palmitate; isopropyl myristate; isopropyl isostearate; diethyl sebacate; diisopropyl adipate; tocopheryl acetate; tocopheryl linoleate; hexadecyl stearate; ethyl lactate; cetyl oleate; cetyl ricinoleate; oleyl alcohol; hexadecyl alcohol; octyl hyroxystearate; octyl dodecanol; wheat germ oil; hydrogenated vegetable oils; castor oil; petrolatum; modified lanolins; branched-chain hydrocarbons; alcohols and esters; corn oil; cottonseed oil; olive oil; palm kernel oil; rapeseed oil; safflower oil; jojoba oil; evening primrose oil; avocado oil mineral oil, sheabutter, octylpalmitate, maleated soybean oil, glycerol trioctanoate, diisopropyl dimerate, and volatile and non-volatile silicone oils including phenyl trimethicone.
Suitable oils for use herein are acetylglycerides, octanoates, and decanoates of alcohols and polyalcohols, such as those of glycol and glycerol, the ricinoleates of alcohols and polyalcohols such as cetyl ricinoleate, PG-3 diisostearate, polyglycerol ethers, polyglyerol esters, caprylic triglycerides, capric triglycerides, isostearic triglyceride, adipic triglyceride, phenyl trimethicone, lanolin oil, polybutene, isopropyl palmitate, isopropyl isostearate, cetyl ricinoleate, octyl dodecanol, oleyl alcohol, hydrogenated vegetable oils, castor oil, modified lanolins, octyl palmitate, lanolin oil, maleated soybean oil, cetyl ricinoleate, glyceryl trioctanoate, diisopropyl dimerate, synthetic lanolin derivatives and branched chain alcohols, sucrose esters of fatty acids, octyl hydroxystearate and mixtures thereof.
Preferably, the oils used are selected such that the majority (at least about 75%, preferably at least about 80% and most preferably at least about 99%) of the types of oils used have solubility parameters that do not differ by more than from about 1 to about 0.1, preferably from about 0.8 to about 0.1.
A surfactant may also be added to compositions of the invention, in order to confer beneficial cosmetic or application properties. Surfactants suitable for use are those which can form emulsions and/or association structures. Surfactant emulsifier can be from 0% to about 20% of the formulation, preferably from 0% to about 15% and most preferably from about 1% to about 10%. Examples of suitable emulsifiers can be found in U.S. Pat. No. 5,085,856 to Dunphy et al.; and U.S. Pat. No. 5,688,831 to El-Nokaly et al. Examples of other suitable emulsifiers can be found in Cosmetic Bench Reference, pp. 1.22, 1.24-1.26 (1996), all of which are incorporated herein by reference.
Also useful herein are surfactants that form association structures, preferably lamellar or hexagonal liquid crystals, at ambient temperature when mixed with a polar solvent. Ambient temperature/room temperature as used herein typically means about 20xc2x0 C. Generally ambient temperature can range from about 18xc2x0 C. to about 27xc2x0 C., preferably from about 20xc2x0 C. to about 25xc2x0 C., depending on such variables as geographical location, i.e. sub-tropical vs. temperature regions. One of ordinary skill in art is readily able to determine if association structures form at ambient temperatures. The surfactants suitable for use generally have a Krafft point at or below about ambient temperature about 20xc2x0 C. or generally at or below about 18xc2x0 C. to about 27xc2x0 C., preferably at or below from about 20xc2x0 C. to about 25xc2x0 C.
The definition of Krafft point is well known in the art and one of ordinary skill in the art can readily determine a surfactant""s Krafft point. In general terms, Krafft point is the melting point of the hydrocarbon chains of the surfactants. It can also be expressed as the temperature at which the solubility of an association colloid in water suddenly increases because critical micelle concentration is exceeded and micelles form.
In preparing a sample combination of surfactant and polar solvent to demonstrate the ability to form association structures, the surfactant needs to be sufficiently soluble in the polar solvent such that an association structure can form at ambient temperature. One of ordinary skill in the art is capable of determining compatible interactions.
Any surfactant which forms association structures at ambient temperature and is suitable for use in cosmetics is suitable for use herein. Surfactants suitable for use in cosmetics do not present dermatological or toxicological problems. Anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants and mixtures thereof are suitable for use. Preferably anionic surfactants, nonionic surfactants, cationic surfactants, amphoteric surfactants and mixtures thereof having a Krafft point at or below about ambient temperature are used. More preferably, nonionic surfactants, cationic surfactants, amphoteric surfactants and mixtures thereof having a Krafft point at or below about ambient temperature are used.
The surfactants can be used at levels from about 4% to about 97%, preferably from about 5% to about 95%, more preferably from about 20% to about 90% and most preferably from about 30% to about 70% of the association structure.
The cosmetic compositions of this invention can contain one or more materials, herein singly or collectively referred to as a xe2x80x9csolidifying agentxe2x80x9d, that are effective to solidify the particular liquid base materials to be used in a cosmetic composition. (As used herein, the term xe2x80x9csolidifyxe2x80x9d refers to the physical and/or chemical alteration of the liquid base material so as to form a solid or semi-solid at ambient conditions, i.e., to form a final composition that has a stable physical structure and can be deposited on the skin under normal use conditions.) As is appreciated by those skilled in the art, the selection of the particular solidifying agent for use in the cosmetic compositions will depend upon the particular type of composition desired, i.e., gel or wax-based, the desired rheology, the liquid base material used and the other materials to be used in the composition. The solidifying agent is preferably present at a concentration of from about 0 to about 90%, more preferably from about 1 to about 50%, even more preferably from about 5% to about 40%, most preferably from about 3% to about 20%.
The wax cosmetic stick embodiments of this invention preferably contain from about 5% to about 50% (by weight) of a waxy solidifying agent. By the term xe2x80x9cwaxy solidifying agent,xe2x80x9d as used herein, is meant a solidifying material having wax-like characteristics. Such waxy materials may also serve as emollients. Among the waxy materials useful herein are the high melting point waxes, i.e., having a melting point of from about 65xc2x0 C. to about 125xc2x0 C., such as beeswax, spermaceti, carnauba, baysberry, candelilla, montan, ozokerite, ceresin, paraffin, synthetic waxes such as Fisher-Tropsch waxes, microcrystalline wax, and mixtures thereof. Ceresin, ozokerite, white beeswax, synthetic waxes, and mixtures thereof, are among those useful herein are disclosed in U.S. Pat. No. 4,049,792, Elsnau, issued Sep. 20, 1977, herein incorporated by reference in its entirety). Low melting waxes, having a melting point of from about 37xc2x0 C. to about 75xc2x0 C., are preferred for use in the wax stick embodiments of this invention. Wax stick embodiments of this invention, which contain volatile silicone oils as a liquid base material, preferably contain from about 10% to about 35%, more preferably from about 10% to about 20% (by weight), of a low-melting wax. Such materials include fatty acids, fatty alcohols, fatty acid esters and fatty acid amides, having fatty chains of from about 8 to about 30 carbon atoms, and mixtures thereof. Preferred wax-like materials include cetyl alcohol, palmitic acid, stearyl alcohol, behenamide, sucrose esters of tallow fatty acids, mono and di-fatty acid esters of polyethylene glycol, and mixtures thereof. Stearyl alcohol, cetyl alcohol, and mixtures thereof, are particularly preferred. Additional fatty acids, fatty alcohols, and other wax-like materials useful in this invention are also well known in the art.